Receptor-Mediated Changes in Hepatocyte Phosphoinositide Metabolism

Mechanism and Significance
  • Joseph Eichberg
  • Charles A. Harrington


Hepatocytes respond to a variety of extracellular stimuli which evoke intracellular metabolic changes. Among these, glucagon, isoproterenol, and other β-adrenergic receptor agonists act via elevation of cAMP levels, which leads to activation of glycogen phosphorylase and a resultant onset of glycogenolysis. However, another group of stimuli, which includes α1 adrenergic agonists, vasopressin, and angiotensin II, each acting at a distinct cell surface receptor, enhances glycogen phosphorylase activity in rat hepatocytes. The mechanism is cAMP independent and involves a rapid rise in free cytosolic Ca2+ [6,10,31]. The mechanism of Ca2+ mobilization is unsettled, but cumulative evidence suggests that the ion is released from at least one and possible several intracellular sites. An increase in cytosolic Ca2+ may also constitute a step in the initiation of other cellular events such as inactivation of glycogen synthetase and stimulation of potassium fluxes across the plasma membrane [10]. The release of Ca2+ into the cytosol appears to be followed by extensive net uptake of the ion from the external medium, perhaps to replenish depleted intracellular stores.


Phosphatidic Acid Glycogen Phosphorylase Inositol Phospholipid Inositol Polyphosphates Phosphoinositide Metabolism 
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  1. 1.
    Agranoff, B. W.; Murthy, P.; Sequin, E. P. Thrombin-induced phosphodiesteratic cleavage of phosphatidylinositol bisphosphate in human platelets. J. Biol. Chem 258: 2076–2078, 1983.PubMedGoogle Scholar
  2. 2.
    Berridge, M. J. Phosphatidylinositol hydrolysis: A multifunctional hypothesis. Mol. Cell. Endocrinol 24: 115–140, 1981.PubMedCrossRefGoogle Scholar
  3. 3.
    Berridge, M. J. Rapid accumulation of inositol trisphosphate reveals that agonists hydrolyse polyphosphoinositides instead of phosphatidylinositol. Biochem. J 212: 849–858, 1983.Google Scholar
  4. 4.
    Berridge, M. J.; Dawson, R. M. C.; Downes, C. P.; Heslop, J. P.; Irvine, R. F. Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phsophoinositides. Biochem. J 212: 473–482, 1983.PubMedGoogle Scholar
  5. 5.
    Billah, M. M.; Michell, R. H. Phosphatidylinositol metabolism in rat hepatocytes stimulated by glycogenolytic hormones. Biochem. J 182: 661–668, 1979.PubMedGoogle Scholar
  6. 6.
    Blackmore, P. F.; Hughes, B. P.; Shuman, E. A.; Exton, J. H. a-Adrenergic activation of phosphorylase in liver cells involves mobilization of intracellular calcium without influx of extracellular calcium. J. Biol. Chem 257: 190–197, 1982.PubMedGoogle Scholar
  7. 7.
    Charest, R.; Blackmore, P. F.; Berthon, B.; Exton, J. H. Changes in free cytosolic Ca2+ in hepatocytes following aradrenergic stimulation. J. Biol. Chem 258: 8769–8773, 1983.PubMedGoogle Scholar
  8. 8.
    Creba, J. A.; Downes, C. P.; Hawkins, P. T.; Brewster, G.; Michell, R. H.; Kirk, C. J. Rapid breakdown of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate in rat hepatocytes stimulated by vasopressin and other Ca2+-mobilizing hormones. Biochem. J 212: 733–747, 1983.PubMedGoogle Scholar
  9. 9.
    De Torrontegui, G.; Berthet, J. The action of adrenaline and glucagon on the metabolism of phospholipids in the rat liver. Biochim. Biophys. Acta 116: 467–476, 1966.PubMedGoogle Scholar
  10. 10.
    Exton, J. H. Molecular mechanisms involved in α1 aradrenergic responses. Mol. Cell. Endocrinol 23: 233–264, 1981.PubMedCrossRefGoogle Scholar
  11. 11.
    Fain, J. N.; Lin, S.-H.; Randazzo, P.; Robinson, S.; Wallace, M. Hormonal regulation of glycogen phosphorylase in rat hepatocytes: Activation of phosphatidylinositol breakdown by vasopressin and alpha1 catecholamines. In: Isolation, Characterization and Use of Hepatocytes, R. A. Harris and N. W. Cornell, eds., New York, Elsevier Biomedical, 1983, pp. 411–418.Google Scholar
  12. 12.
    Harrington, C. A.; Eichberg, J. Norepinephrine causes aradrenergic receptor-mediated decrease of phosphatidylinositol in isolated rat liver plasma membranes supplemented with cytosol. J. Biol. Chem 258: 2087–2090, 1983.PubMedGoogle Scholar
  13. 13.
    Harrington, C. A.; Davis, C. M.; Eichberg, J. arAdrenergic receptor-mediated phosphatidylinositol metabolism in rat hepatocytes and purified plasma membranes. Abstr. 63rd Annual Endocrine Meeting, p. 113, 1981.Google Scholar
  14. 14.
    Harrington, C. A.; Fenimore, D. C.; Eichberg, J. Fluorometric analysis of polyunsaturated phosphatidylinositol and other phospholipids in the picomole range using high-performance thin layer chromatography. Anal. Biochem 106: 307–313, 1980.PubMedCrossRefGoogle Scholar
  15. 15.
    Helmkamp, G. M.; Harvey, M. S.; Wirtz, K. W. A.; Van Deenen, L. L. M. Phospholipid exchange between membranes: Purification of bovine brain proteins that preferentially catalyze the transfer of phosphatidylinositol. J. Biol. Chem 249: 6382–6389, 1974.PubMedGoogle Scholar
  16. 16.
    Howard, R. B.; Lee, J. C.; Pesch, L. R. A. The fine structure, potassium content, and respiratory activity of isolated rat liver parenchymal cells prepared by improved enzymatic techniques. J. Cell Biol 57: 642–658, 1973.PubMedCrossRefGoogle Scholar
  17. 17.
    Kirk, C. J. Ligand-stimulated inositol lipid metabolism in the liver: Relationship to receptor function. Cell Calcium 3: 399–411, 1982.PubMedCrossRefGoogle Scholar
  18. 18.
    Kirk, C. J.; Michell, R. H.; Hems, D. A. Phosphatidylinositol metabolism in rat hepatocytes stimulated by vasopressin. Biochem. J 194: 155–165, 1981.PubMedGoogle Scholar
  19. 19.
    Kirk, C. J.; Verrinder, T. R.; Hems, D. A. Rapid stimulation, by vasopressin and adrenaline, of inorganic phosphate incorporation into phosphatidylinositol in isolated hepatocytes. FEBS Lett. 83: 267–271, 1977.PubMedCrossRefGoogle Scholar
  20. 20.
    Lin, S.-H.; Fain, J. N. Vasopressin and epinephrine stimulation of phosphatidylinositol breakdown in the plasma membrane of rat hepatocytes. Life Sci. 29: 1905–1912, 1981.PubMedCrossRefGoogle Scholar
  21. 21.
    Michell, R. H. Inositol phospholipids and cell surface receptor function. Biochim. Biophys. Acta 415: 81–147, 1975.PubMedGoogle Scholar
  22. 22.
    Michell, R. H. Inositol phospholipids in membrane function. Trends Biochem. Sci 4: 128–131, 1979.CrossRefGoogle Scholar
  23. 23.
    Michell, R. H.; Kirk, C. J.; Jones, L. M.; Downes, C. P.; Creba, J. A. The stimulation of inositol lipid metabolism that accompanies calcium mobilization in stimulated cells: Defined characteristics and unanswered questions. Philos. Trans. R. Soc. London Ser. B 296: 123–137, 1981.CrossRefGoogle Scholar
  24. 24.
    Pohl, S. L.; Birnbaumer, L.; Rodbell, M. J. The glycogen-sensitive adrenyl cyclase system in plasma membranes of rat liver. J. Biol. Chem 246: 1849–1856, 1971.PubMedGoogle Scholar
  25. 25.
    Prpic, V.; Blackmore, P. F.; Exton, J. H. Phosphatidylinositol breakdown induced by vasopressin and epinephrine in hepatocytes is calcium-dependent. J. Biol. Chem 257: 11323–11331, 1982.PubMedGoogle Scholar
  26. 26.
    Rhodes, D.; Prpic, V.; Exton, J. H.; Blackmore, P. F. Stimulation of phosphatidylinositol-4,5-bisphosphate hydrolysis in hepatocytes by vasopressin. J. Biol. Chem 258: 2770–2773, 1983.PubMedGoogle Scholar
  27. 27.
    Thomas, A. P.; Marks, J. S.; Coll, K. E.; Williamson, J. R. Quantitation and early kinetics of inositol lipid changes induced by vasopressin in isolated and cultured hepatocytes. J. Biol. Chem 258: 5716–5725, 1983.PubMedGoogle Scholar
  28. 28.
    Tolbert, M. E. M.; White, A. C.; Aspry, K.; Curtis, J.; Fain, J. N. Stimulation by vasopressin and a- catecholamines of phosphatidylinositol formation in isolated rat liver parenchymal cells. J. Biol. Chem 257: 1938–1944, 1980.Google Scholar
  29. 29.
    Wallace, M. A.; Poggioli, J.; Gireaud, F.; Claret, M. Norepinephrine-induced loss of phosphatidylinositol from isolated rat liver plasma membranes: Effect of divalent cations. FEBS Lett. 156: 239–243, 1983.PubMedCrossRefGoogle Scholar
  30. 30.
    Wallace, M. A.; Randazzo, P.; Li, S.-Y.; Fain, J. Direct stimulation of phosphatidylinositol degradation by addition of vasopressin to purified rat liver plasma membranes. Endocrinology 111: 341–343, 1982.PubMedCrossRefGoogle Scholar
  31. 31.
    Williamson, J. R.; Cooper, R. H.; Hoek, J. B. Role of calcium in the hormonal regulation of liver metabolism. Biochim. Biophys. Acta 639: 243–295, 1981.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • Joseph Eichberg
    • 1
  • Charles A. Harrington
    • 2
  1. 1.Department of Biochemical and BioPhysical SciencesUniversity of HoustonHoustonUSA
  2. 2.Analytical Neurochemistry LaboratoryTexas Research Institute of Mental SciencesHoustonUSA

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